US3609155A - 1-para-chlorophenyl-1,5,6,7,8,8{11 -hexahydroimidazo{8 1,5-{11 {9 pyridines and intermediates therefor - Google Patents

1-para-chlorophenyl-1,5,6,7,8,8{11 -hexahydroimidazo{8 1,5-{11 {9 pyridines and intermediates therefor Download PDF

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US3609155A
US3609155A US816404A US3609155DA US3609155A US 3609155 A US3609155 A US 3609155A US 816404 A US816404 A US 816404A US 3609155D A US3609155D A US 3609155DA US 3609155 A US3609155 A US 3609155A
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chlorophenyl
hexahydroimidazo
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Albert J Frey
Robert E Manning
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Sandoz AG
Sandoz Wander Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This disclosure pertains to novel l-substituted 2- unsubstituted imidazopyridines, for example l-p-chlorophenyl-3-loweralkylthio-l ,5,6,7,8,8a-hexahydroimidazo[ l ,5-a]pyridene. These compounds are useful as hypotensivc agents.
  • This invention is directed to novel heterocyclic compounds and more particularly to novel substituted imidazopyridines. Still more particularly, this invention pertains to a l-pchlorophenyl-2unsubstituted-3-hydrazinoimidazo[ l ,S-a ]pyridine. This invention also concerns methods for preparing said compound, intermediates therefor, and to methods for preparing said intermediates.
  • the 3-hydrazino imidazo pyridine of this invention may be represented by the formula
  • This compound (I) is prepared by treating a corresponding 3- lower alkylthio imidazopyridine intermediate with hydrazine.
  • This intermediate may be prepared by reaction of pchlorophenyl-Z-pyridyl ketone and hydroxylamine hydrochloride to obtain a corresponding oxime, treating this p-chlorophenyl-Z-pyridyl oxime with hydrogen in the presence of precious metal catalyst to obtain p-chlorophenyl- 2-piperidyl methylamine, and treating said methylamine with carbon disulfide and raising the temperature of the mixture to obtain a 3-thioxo imidazopyridine.
  • This compound is then treated with a lower alkyl halide to obtain the corresponding 3lower alkylthio imidazopyridine intermediate referred to above.
  • the process for preparing the B-hydrazino imidazopyridine of this invention (1) may be represented by the following reaction scheme.
  • R in the above process represents loweralkyl, i.e., alkyl having one to five carbon atoms such as methyl, ethyl, isopropyl and the like.
  • a lower alkylthio imidazopyridine (ll) is treated with hydrazine at an elevated temperature.
  • a temperature of about 70 to 120 C. is satisfactory although a temperature of about 90 to 1 10 C. is preferred.
  • Solvent such as alcohol may be used but is not considered necessary as it is preferred to simply use excess hydrazine reactant.
  • the exact temperatures used are not critical to the successful completion of the process.
  • the 1-pchlorophenyl-B-hydrazinol ,5 ,6,7,8,8a-hexahydroimidazo[ll l,5-a]pyridine is readily recovered, e.g., in the form of its hydrochloride, using conventional recovery techniques.
  • the compounds of Formula (ll) are prepared according to a multistep process which involves the treating of p-chlorophenyl-Zpyridyl ketone (III), which is available commercially with hydroxylamine hydrochloride in the presence of a weak base, such as sodium acetate, and solvents such as lower alkanols, e.g., ethanol, ether, tetrahydrofuran and the like (Step 1).
  • the reaction temperature is preferably room temperature to the reflux temperature of the solvent, and desirably temperatures of about 20 to C. may be utilized.
  • This oxime (W) is hydrogenated (Step 2) over precious metal catalyst such as platinum oxide in acid medium, e.g., glacial acetic acid, in order to provide compound (V).
  • the hydrogen utilized is preferably maintained at atmospheric pressure and pressures of about 700 to 10,000 mm. Hg. may be used. Conveniently, this process may be conducted at room temperature with temperatures of about l0 to 50 C. providing satisfactory results. Conventional recovery techniques are utilized for obtaining the product.
  • the compound of Formula (Vl) is obtained from the methylamine of Formula (V) by treating the latter with carbon disult'tde in solvent such as ether, tetrahydrofuran, aromatic hydrocarbons and the like (Step 3).
  • the reaction conveniently takes place at room temperatures although reaction temperatures of about 0 to 60 C. may be used.
  • the product is then cooled in an ice bath with stirring for about 2 hours.
  • the resulting material is then heated at a temperature from about l00 to 200 C., preferably 120 to 180 C., for about 1 to 3 hours.
  • the 3-thioxo imidazo [LS-alpyridine (Vl) is recovered by conventional recovery techniques.
  • the last stage (Step 4) of the process for preparing the 3-lower alkylthio imidazopyridine of Formula (ll) involves treating the 3-thioxo compound (Vl) with a loweralkyl halide, e.g., methyliodide, in solvent at elevated temperatures.
  • Solvents such as lower alkanols, e.g., methanol and ethanol, or tetrahydrofuran, ether, aromatic hydrocarbons, e.g., benzene, and the like may be employed.
  • a temperature of about 70 to about 100 C., and preferably about 40 to about 80 C. may be utilized.
  • the product (ll) is "then recovered using conventional techniques such a concentration, crystallization and the like.
  • the imidazopyridines represented by Formulas (l), (ll) and (VI) above are useful because they possess pharmacological properties in animals, such as in mammals.
  • these compounds are active hypotensive agents as indicated by their activity in anesthetized dog tested by blood pressure measurement using a mercury manometer or transducer via a catheter inserted in the carotid or femoral artery.
  • the compounds may be combined with one or more pharmaceutically acceptable carriers or adjuvants. They may be administered orally or parenterally and, depending upon the compound employed and the mode of administration, the exact dosage utilized may vary.
  • compounds (I) and (ll) may be similarly administered in the form of their nontoxic pharmaceutically acceptable acid addition salts.
  • Such salts possess the same order of actively as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly are included within the scope of the invention.
  • Representative of such salts are the mineral acid salts, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzene-sulfonate and the like.
  • succinate benzoate, acetate, p-toluenesulfonate, benzene-sulfonate and the like.
  • This daily dosage is preferably administered 3 to 5 times a day, or in sustained release form.
  • the daily dosage is from about 50 milligrams to about 60 milligrams.
  • Dosage forms suitable for internal use compriseabout milligrams to about milligrams of the active compound in intermediates administered with a solid or liquid pharmaceutically acceptable carriers or diluents.
  • a representative formulation suitable for oral administration is a tablet prepared by standard tabletting techniques which contains the foliowing:
  • Step 3 l-p-chlorophenyl-Zi-thioxo-l,2,3,5,6,7,8,8,aoctahy droimidazol l, S-alpyridine
  • a solution of carbon disulfide (3.2 g.) in ether is added dropwise over 5 minutes to a stirred solution of p-chlorophenyI-Z-piperidyl methylamine (crude 8.8 g.) in ether (120 ml.) and cooled in an ice bath. After stirring for one-half hour, the resultant solid is collected and heated in oil bath at l40 for 2 hours. The cooled mass is crystallized twice from methanol to give 5 g.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This disclosure pertains to novel 1-substituted 2-unsubstituted imidazopyridines, for example 1-p-chlorophenyl-3-loweralkylthio1,5,6,7,8,8a-hexahydroimidazo(1,5 -a)pyridene. These compounds are useful as hypotensive agents.

Description

United States Patent {72] Inventors Albert J. Frey Essex Fells; Robert E. Manning, Mountain Lake, both of NJ.
[2]] Appl. No. 816,404
[22] Filed Apr. 15, 1969 [23] Division of Ser. No. 672,990,
Pat. No. 3,467,662
[45] Patented Sept. 28, 1971 [7 3] Assignee Sandoz-Wander, Inc.
Hanover, NJ.
[54] l-PARA-CHLOROPHENYL-l,5,6,7,8,8a
HEXAHYDROIMIDAZO[1,5 a ]PYRIDlNES AND INTERMEDIATES THEREFOR 5 Claims, No Drawings s2 U.S.Cl ..260/293 on,
260/293 DC, 260/293.4 R, 260/293.4 F,
OTHER REFERENCES Adamson et al., J. Chem. Soc. I957, 23 I5, 23- 24. Morrison et al., Organic Chemistry," 2nd Edition Allyn and Bacon, lnc., Boston, 1966, p. 646.
Primary ExaminerJohn D. Randolph Assistant Examiner-G. Thomas Todd ArtorneysGerald D. Sharkin, Frederick H. Weinfeldt,
Robert S. Honor, Walter F. Jewell and Richard E. Vila ABSTRACT: This disclosure pertains to novel l-substituted 2- unsubstituted imidazopyridines, for example l-p-chlorophenyl-3-loweralkylthio-l ,5,6,7,8,8a-hexahydroimidazo[ l ,5-a]pyridene. These compounds are useful as hypotensivc agents.
l-PARA-CHLOROPHENYL-l ,5,6,7,8,8 HEXAHYDROIMIDAZOl 1,5- 1PYRIDINES AND INTERMEDIATES THEREFOR This application is a division of application Ser. No. 672,990, filed Oct. 5, 1967, now U.S. Pat. No. 3,467,662.
This invention is directed to novel heterocyclic compounds and more particularly to novel substituted imidazopyridines. Still more particularly, this invention pertains to a l-pchlorophenyl-2unsubstituted-3-hydrazinoimidazo[ l ,S-a ]pyridine. This invention also concerns methods for preparing said compound, intermediates therefor, and to methods for preparing said intermediates.
The 3-hydrazino imidazo pyridine of this invention may be represented by the formula This compound (I) is prepared by treating a corresponding 3- lower alkylthio imidazopyridine intermediate with hydrazine. This intermediate may be prepared by reaction of pchlorophenyl-Z-pyridyl ketone and hydroxylamine hydrochloride to obtain a corresponding oxime, treating this p-chlorophenyl-Z-pyridyl oxime with hydrogen in the presence of precious metal catalyst to obtain p-chlorophenyl- 2-piperidyl methylamine, and treating said methylamine with carbon disulfide and raising the temperature of the mixture to obtain a 3-thioxo imidazopyridine. This compound is then treated with a lower alkyl halide to obtain the corresponding 3lower alkylthio imidazopyridine intermediate referred to above.
The process for preparing the B-hydrazino imidazopyridine of this invention (1) may be represented by the following reaction scheme.
R in the above process represents loweralkyl, i.e., alkyl having one to five carbon atoms such as methyl, ethyl, isopropyl and the like.
In accordance with the above-depicted process, a lower alkylthio imidazopyridine (ll) is treated with hydrazine at an elevated temperature. A temperature of about 70 to 120 C. is satisfactory although a temperature of about 90 to 1 10 C. is preferred. Solvent such as alcohol may be used but is not considered necessary as it is preferred to simply use excess hydrazine reactant. Moreover, the exact temperatures used are not critical to the successful completion of the process. The 1-pchlorophenyl-B-hydrazinol ,5 ,6,7,8,8a-hexahydroimidazo[ll l,5-a]pyridine is readily recovered, e.g., in the form of its hydrochloride, using conventional recovery techniques. Standard methods may be used to convert this acid addition salt to the free base, e.g., it may be admixed with aqueous sodium carbonate and ether and the ether evaporated to provide the crystalline free base. The 3-lower alkylthio imidazopyridine starting compound for the process described above is prepared as indicated by the following diagram:
l Step 1 l 1 l l \N I N-OH (III) (I J'Step2 \Step4 l I I N RS The compounds of Formula (ll) are prepared according to a multistep process which involves the treating of p-chlorophenyl-Zpyridyl ketone (III), which is available commercially with hydroxylamine hydrochloride in the presence of a weak base, such as sodium acetate, and solvents such as lower alkanols, e.g., ethanol, ether, tetrahydrofuran and the like (Step 1). The reaction temperature is preferably room temperature to the reflux temperature of the solvent, and desirably temperatures of about 20 to C. may be utilized. Neither the reaction temperature nor the solvent is critical in the obtaining of the oxime (IV). This oxime (W) is hydrogenated (Step 2) over precious metal catalyst such as platinum oxide in acid medium, e.g., glacial acetic acid, in order to provide compound (V). The hydrogen utilized is preferably maintained at atmospheric pressure and pressures of about 700 to 10,000 mm. Hg. may be used. Conveniently, this process may be conducted at room temperature with temperatures of about l0 to 50 C. providing satisfactory results. Conventional recovery techniques are utilized for obtaining the product.
The compound of Formula (Vl) is obtained from the methylamine of Formula (V) by treating the latter with carbon disult'tde in solvent such as ether, tetrahydrofuran, aromatic hydrocarbons and the like (Step 3). The reaction conveniently takes place at room temperatures although reaction temperatures of about 0 to 60 C. may be used. The product is then cooled in an ice bath with stirring for about 2 hours. The resulting material is then heated at a temperature from about l00 to 200 C., preferably 120 to 180 C., for about 1 to 3 hours. The 3-thioxo imidazo [LS-alpyridine (Vl) is recovered by conventional recovery techniques. The last stage (Step 4) of the process for preparing the 3-lower alkylthio imidazopyridine of Formula (ll) involves treating the 3-thioxo compound (Vl) with a loweralkyl halide, e.g., methyliodide, in solvent at elevated temperatures. Solvents such as lower alkanols, e.g., methanol and ethanol, or tetrahydrofuran, ether, aromatic hydrocarbons, e.g., benzene, and the like may be employed. Although neither the solvent nor the temperature utilized is critical, a temperature of about 70 to about 100 C., and preferably about 40 to about 80 C. may be utilized. The product (ll) is "then recovered using conventional techniques such a concentration, crystallization and the like.
Compound (I) and (VI) above may also be represented by their respective tautomeric equivalents as follows (VIA) In order to simplify this description, however, Formulas (I) and (Vi) only will be used, but it should be understood that either of the tautomeric forms may be represented.
The compounds of Formulas (I), (ll) and (VI) exist as stereoisomers. Separation and recovery of the respective isomers may be readily accomplished employing conventional techniques and all the isomers are included within the scope of this invention.
The imidazopyridines represented by Formulas (l), (ll) and (VI) above are useful because they possess pharmacological properties in animals, such as in mammals. In particular, these compounds are active hypotensive agents as indicated by their activity in anesthetized dog tested by blood pressure measurement using a mercury manometer or transducer via a catheter inserted in the carotid or femoral artery. When used as hypotensives, the compounds may be combined with one or more pharmaceutically acceptable carriers or adjuvants. They may be administered orally or parenterally and, depending upon the compound employed and the mode of administration, the exact dosage utilized may vary. Furthermore, compounds (I) and (ll) may be similarly administered in the form of their nontoxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of actively as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzene-sulfonate and the like. In general, satisfactory results are obtained when these compounds are administered at daily dosage of about 1 milligram to about 10 milligrams per kilogram of animal body weight. This daily dosage is preferably administered 3 to 5 times a day, or in sustained release form. For more large mammals, the daily dosage is from about 50 milligrams to about 60 milligrams. Dosage forms suitable for internal use compriseabout milligrams to about milligrams of the active compound in intermediates administered with a solid or liquid pharmaceutically acceptable carriers or diluents.
A representative formulation suitable for oral administration is a tablet prepared by standard tabletting techniques which contains the foliowing:
Ingredient Parts by Weight 1 p-chlorop henyl-3-hydrozinn- 1,5 ,6,7,8,8a-hexahydroimidazo[1,5
The following example is provided for the purpose of illustration and not by way of limitation. It is not intended so as to limit the scope of the invention as defined in the appended claims.
EXAMPLE Step I. p-chlorophenyl-Z-pyridyl oxime l NH:
A mixture of this crude oxime (25 g.) obtained according to Step l, platinum oxide (0.2 g.) and glacial acetic acid (50 ml.) is agitated under an atmosphere of hydrogen (50 p.s.i.) at room temperature overnight. The reaction mixture is filtered and the filtrate evaporated in vacuo. The residue is dissolved in water, made basic with sodium carbonate solution and extracted with methylene chloride. The extract was dried using sodium sulfate and evaporated to give the crude product pchlorophenyl-Z-piperidyl methylamine, (14 g.) as an oil which is used directly for the next step.
Step 3. l-p-chlorophenyl-Zi-thioxo-l,2,3,5,6,7,8,8,aoctahy droimidazol l, S-alpyridine A solution of carbon disulfide (3.2 g.) in ether is added dropwise over 5 minutes to a stirred solution of p-chlorophenyI-Z-piperidyl methylamine (crude 8.8 g.) in ether (120 ml.) and cooled in an ice bath. After stirring for one-half hour, the resultant solid is collected and heated in oil bath at l40 for 2 hours. The cooled mass is crystallized twice from methanol to give 5 g. substantially 1-p-chlorophenyl-3-thioxol,2,3,5,6,7,8,8a-octal1ydroimidam[ l, 5]pyridine m.p. 191 to 192 C. (stereoisomer A). Recrystallization of the first mother liquor from acetonitrile-ether (1:2) several times gives mg. substantially pure stereoisomer B; m.p. 176 to WT C. Step 4A. l-p-chlorophenylS-methylthio-l ,,5,6,7,8,8a-hexahydroimidaz0[ 1,5-a pyridine (stereoisomer A) A mixture of l-p-chlorophenyl-3 1-thioxo-l,2,3 ,5,6,'7,8,8aoctahydroimiddazofl,Se-alpyridine (ll g. stereoisomer A) methyliodide (1 l g.) and methanol ml.) is heated under reflux for 2 hours. The reaction mixture is evaporated in vacuo and the residue is dissolved in ether (200 ml.) and 1N sodium carbonate (100 ml.). The ether phase is dried with sodium sulfate and evaporated to give 13 g. of an oil which upon recrystallization from pentane, affords llg. of l-pchlorophenyl-3-methylthio-l ,5 ,6,7 ,8,8a-hexahydruimidazo[l,5-a]pyridine (stereoisomer A); m.p. 96 to 97 C. Step 48. l-p-chlorophenyl-3-methylthio-l,5,6,7,8,8ahexahydrolmldazo l,5-a]pyridine (stereoisomer B) CII3S J:
A mixture of l-p-chlorophenyl-3-methylthio-l, 5, 6, 7, 8, 8a-hexahydroimldam[ l,5-a]pyridine (10.5 g.; stereoisomer A) and 97 percent hydrazine (60 ml.) is stirred under rcflux for 2 hours. The reaction mixture is cooled and diluted with water (50 ml. ).The resultant crystals are collected by filtration and dried overnight in vacuo. The resultant matcrial (9.5 g.) is dissolved in a mixture of ethanol-ether I12) and treated with excess hydrogen chloride gas to give a crystalline solid. Recrystallization from ethanol-ether (1:2) affords 7.l g. of lp-chlorophenyl-3hydrazino-l, 5, 6, 7, 8, 8a-hexahydroimidazo[ l ,S-alpyridine dihydrochloride; m.p. l l3l l 7C.
What is claimed is: t
l. l-p-Chlorophenyl-3-loweralkylthio-l ,5,6,7,8,8a-hexahydroimidazo[ l,5-a]pyridine.
2. 1-p-Chlorophenyl-3-methylthio-l ,5,6,7,8,8a-hexahydroimidazo[ l. S-alpyridine.
3. l-p-Chlor0phenyl-3-thi0xo- 1 ,2,3,5 ,6,7,8,8a-0ctahydroimidazo[ l ,5-a]pyridine.
4. A nontoxic pharmaceutically acceptable acid addition salt of the compound of claim 1.
5. p-Chlorophenyl-2-piperidyl methylamine.

Claims (4)

  1. 2. 1-p-Chlorophenyl-3-methylthio-1,5,6,7,8,8 Alpha -hexahydroimidazo( 1,5- Alpha )pyridine.
  2. 3. 1-p-Chlorophenyl-3-thioxo-1,2,3,5,6,7,8,8 Alpha -octahydroimidazo(1,5- Alpha )pyridine.
  3. 4. A nontoxic pharmaceutically acceptable acid addition salt of the compound of claim 1.
  4. 5. p-Chlorophenyl-2-piperidyl methylamine.
US816404A 1969-04-15 1969-04-15 1-para-chlorophenyl-1,5,6,7,8,8{11 -hexahydroimidazo{8 1,5-{11 {9 pyridines and intermediates therefor Expired - Lifetime US3609155A (en)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Adamson et al., J. Chem. Soc. 1957, 2315, 23 24. *
Morrison et al., Organic Chemistry, 2nd Edition Allyn and Bacon, Inc., Boston, 1966, p. 646. *

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